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Despite the available treatment options available for cardiovascular disease, acute coronary syndrome (ACS) is the leading cause of death in the industrialized world. ACS occurs as a result of thrombus formation within the lumen of a coronary artery, which is associated with chronic inflammation within the wall of the artery. Arterial inflammation is initiated by the formation of a lipid core and infiltration of inflammatory cells leading to plaque formation. Unstable plaques contain a substantial necrotic core and apoptotic cells that disrupt the endothelium and can lead to plaque rupture exposing of underlying collagen, von Willebrand factor (vWF), tissue factor, lipids and smooth muscle allowing initiation of platelet adhesion, activation, and aggregation (Libby et al. 1996. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol 7, 330-335). ACS is treated with a combination of anti-platelet therapies, cholesterol lowering medications (e.g. statins), anti-coagulants, as well as surgical recanalization through percutaneous coronary intervention (PCI) and implantation of stents.
Anti-platelet therapies such as COX-1 inhibitors (e.g. aspirin), ADP receptor antagonists (e.g. Ticlopedine and clopidogrel), and glycoprotein IIb/IIIa receptor antagonists have been shown to reduce the incidence of major adverse coronary events (MACE) in a number of different clinical trials (Dupont et al-2009-Antiplatelet therapies and the role of antiplatelet resistance in acute coronary syndrome. Thromb Res 124, 6-13). However, a proportion of patients on long-term anti-platelet therapy continue to have cardiovascular events. Moreover, chronic prevention therapy may take up to two years to show maximum beneficial effects, and many patients are then still at high risk for recurrent disease. There is a period of up to 6-12 months after a myocardial infarction that the patient is susceptible to further MACE, frequently due to re-occlusion due to restenosis (Tabas. 2010. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10, 36-46).
Consequently, there is a significant need for treatments directed specifically at preventing further plaque progression and promoting plaque regression could substantially lower events during this period.
Phosphorylcholine, a polar head group on certain phospholipids, has been extensively implicated in cardiovascular disease. Reactive oxygen species generated during coronary inflammation causes the oxidation of low density lipoprotein (LDL) to generate oxidized LDL (oxLDL). In fact, cardiovascular diseases (CVD) such as atherosclerosis, unstabile angina, or acute coronary syndrome have been shown to be associated with elevated plasma levels of oxLDL (Itabe and Ueda. 2007. Measurement of plasma oxidized low-density lipoprotein and its clinical implications. J Atheroscler Thromb 14, 1-11). LDL is a circulating lipoprotein particle that contains lipids with a PC polar head group and an apoB100 protein.
During oxidation of LDL PC containing neo-epitopes that are not present on unmodified LDL, are generated. Newly exposed PC on oxLDL is recognized by scavenger receptors on macrophages, such as CD36, and the resulting macrophage-engulfed oxLDL proceeds towards the formation of pro-inflammatory foam cells in the vessel wall. Oxidized LDL is also recognized by receptors on endothelial cell surfaces and has been reported to stimulate a range of responses including endothelial dysfunction, apoptosis, and the unfolded protein response (Gora et al. 2010. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling. FASEB J 24(9):3284-97). PC neo-epitopes are also exposed on LDL following modification with phospholipase A2 or amine reactive disease metabolites, such as aldehydes generated from the oxidation of glycated proteins. These alternately modified LDL particles are also pro-inflammatory factors in CVD.
Antibodies towards phosphorylcholine (PC) have been shown to bind oxidized, or otherwise modified, LDL and block the pro-inflammatory activity of oxLDL in in vivo models or in vitro studies (Shaw et al. 2000. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 105, 1731-1740; Shaw et al. 2001. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 21, 1333-1339.
Furthermore, an examination of clinical data has demonstrated that low levels of natural IgM anti-PC antibodies are associated with an increased risk of MACE in ACS patients (Frostegard, J. 2010. Low level natural antibodies against phosphorylcholine: a novel risk marker and potential mechanism in atherosclerosis and cardiovascular disease. Clin Immunol 134, 47-54).
Accordingly, there is a need for anti-PC antibody molecules that can be effectively used in therapy, particularly fully human anti-PC antibodies suitable for human therapy. To the applicant's knowledge, to date the art has failed to provide therapeutically efficacious human anti-PC antibodies. The identification of such antibodies has been hampered by the fact that in vitro screening methods for human antibodies with anti-PC binding activity are poor predictors of in vivo therapeutic activity.
In view of this, there is a need in the art for human anti-PC antibody molecules that provide effective and advantageous properties when used in in vivo systems, in particular when administered to humans for therapy.